Eye Banking in the 21St Century: How Far Have We Come? Are We Prepared for What’S Ahead? Donald J

INTERNATIONAL JOURNAL OF EYE BANKING

LITERATURE REVIEW

Eye Banking in the 21st Century: How Far Have We Come? Are We Prepared for What’s Ahead? Donald J. Doughman, MD; Cindy Christian Rogers, MA

ABSTRACT PURPOSE: This review of milestones in eye banking describes efforts by the eye banking community to ensure the quality and quantity of corneal tissue over the last century and anticipates key challenges going forward. METHODS: This account draws on a review of the scientific literature, public documents, and eye banking statistics and is augmented by the recollection of the author, discussions with eye bankers, and an analysis of press- ing medical and nonmedical issues that will bear on the future success of eye banking in the United States and internationally. RESULTS: The author identifies five eras of eye banking, highlighting scientific breakthroughs in surgical techniques, storage, and instrumentation; the professionalization of eye banks through development of medical standards and accreditation programs; and the advent of laws and regulations leading to reimbursement changes and donor legislation. The author next identifies five strengths exhibited by the community to achieve those milestones and delineates crucial questions posed by an ever-expanding array of unprecedented demographic, socioeconomic, geopolitical, biological, regulatory, technological, cultural, and ethical challenges. CONCLUSIONS: Technological advances and collaborative efforts have brought the eye banking community to the enviable position it enjoys today. Only by building on its historical strengths can eye banking professionals worldwide successfully evolve their role in an increasingly complex future.

KEYWORDS: corneal endothelium, corneal preservation, corneal transplantation, eye banks, eye donation, healthcare economics

reserving and restoring vision impaired by cor- on the healthcare delivery system in the United States neal disease, disorder, or injury have never been and elsewhere, the picture is about to change. Add to Pso routine as they are today in the United States, this mix an array of differing cultural expectations, more than 100 years after the first successful penetrat- religious practices, and ethical frameworks, not to ing corneal transplant was performed in 19051 in Eu- mention differing stages of economic development rope. Indeed, for most affluent countries throughout in less affluent countries, and the context for corneal the globe, healthy donor tissue and surgical services transplantation internationally becomes even more are readily available and, for many patients, reason- complicated. Are eye bank and medical professionals ably accessible. Emerging advances in instrumenta- prepared for what lies ahead? tion, surgical technique, and new materials hint at Given the numerous variables in play at this mo- more options and better outcomes for patients and ment in history, the launch of the International Jour- more efficient use of donor tissue by eye banks and nal of Eye Banking provides an opportune time to take surgeons. However, against a backdrop of shifting de- stock of where we have been, where we are, and where mographics, economic uncertainties, and pressures we are going. To this end, this paper (1) reviews the

Author Affiliations: University of Minnesota Department of Corresponding Author: Donald J. Doughman, MD, Min- Ophthalmology and Minnesota Lions Eye Bank (Dr Dough- nesota Lions Eye Bank, 1000 Westgate Dr, Suite 260, St Paul, man); and medical writer/editor and corneal graft recipient MN 55114 ([email protected]). (Ms Rogers).

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technological advances of the last 100 years in tissue Patients undergoing ophthalmic surgical proce- procurement, storage, and surgical techniques and de- dures such as corneal transplants benefited from the scribes how they led to the proliferation of eye banks introduction of antibiotics in the 1930s and cortico- and medical standards, (2) mentions promising de- steroids in the 1940s, as well as the development of velopments in the field, and (3) identifies future chal- more refined surgical instruments and techniques. In lenges, including demographic, socioeconomic, geo- 1939, Weiner and Alois added a beveled edge to the political, ethical, and regulatory issues, made all the trephine, which was first developed by von Hippel more complex by differences among nations, regions, around the turn of the century, thus providing sur- and cultures. A review of this nature, of course, could geons with a tool for better dissection of donor tissue.5 fill a book; however, the purpose here is to sufficiently In Spain, the United Kingdom, Hungary, the United set the stage for the eye banking community to con- States, Switzerland, and Finland, prominent ophthal- sider what questions must be asked and answered as mologists championed corneal transplantation and we move into an uncertain future. continued to refine procedures. Technological advances led to finer sutures and needles; the introduction of the surgical microscope, a major contributor HOW FAR HAVE WE COME? to improving PK outcomes; and a more sophisticated understanding of the role of the cornea’s anatomy he trajectory of eye banking as a professional fo- and physiology, including the critical nature of the T cus has spanned not only many decades but also endothelium.5 many countries, and it represents the contributions of countless individuals dedicated to the mission of pre- The organizing years: 1945–1970 serving and restoring sight. It is perhaps simplest to The ability to store donor corneas even for a short summarize that history by differentiating key periods period of time allowed for the establishment of eye of growth. banks in which tissue could be collected and distributed. The first of these organizations, the Eye-Bank for The formative years: 1935–1944 Sight Restoration, Inc., in New York, was founded in Until the 1930s, surgeons had but one source for pro- 1944 by Richard Townley Paton to “supply donor ma- curing tissue when they needed to perform a corneal terial to qualified surgeons, to support research in and transplant: the eyes of living donors who had been teaching of surgical techniques, to provide ocular tis- enucleated as the result of posterior segment patholo- sue for experimental work, and to stimulate research gy.2 Eyes had to be removed and corneas transplanted in the causes of blindness.”6 Thus, the concept of the immediately, owing to concerns regarding donor tis- eye bank came to be pioneered in the United States; sue death. Although surgeons used only clear corneas, by 1956, the cities of Boston, Philadelphia, Winston- outcomes were relatively limited due to factors such Salem, New Orleans, Chicago, San Francisco, and Los as primitive surgical techniques, intraoperative and Angeles had established eye banks. Moist-chamber postoperative complications, and limited pharmaceu- storage at 4°C continued to be the preservation meth- tical agents, among others. od of choice, while research into alternatives7 (e.g., The event that changed the course of penetrating drying, formalin fixation, freezing, freeze-drying, and keratoplasty (PK) and broke ground for what would liquid paraffin storage) did not produce satisfactory become eye banking occurred in 1937, when Russian results. ophthalmologist Vladimir Filatov reported that ca- During these organizing years, most of the devel- daver tissue stored in a moist chamber at 4°C could opment of eye banks individually as well as nationally successfully be used as donor material.3 Simple, con- continued to take place in the United States. Alson venient, and relatively inexpensive, this storage meth- Braley, the physician-founder of an eye bank in Iowa, od was a marked advance over using tissue from live is credited with stepping up eye banking to a new donors. Nevertheless, it had significant limitations, level of efficiency and reach when he organized vol- particularly the short-term survival of endothelial unteer ham radio operators into a national network cells, a critical factor in maintaining cornea transpar- focused on procurement and placement of eye tissue ency. As a result, corneal transplant surgery continued in the United States.2 Given the urgency of transplant- to be an emergency procedure. Surgeons grafted cor- ing corneal tissue as quickly as possible after donor neas stored at 4°C as soon as possible, usually 24–36 death, the ham radio network offered the most expe- hours post mortem.4 dient method of communicating between eye banks.8 Within 1 year of its founding in 1962, the Eye Bank

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Emergency Network had expanded to 60 operators had limited success in restoring useful vision and were working in 47 cities throughout 26 states.6 used primarily as a tectonic procedure to repair per- The proliferation of eye banks, run almost entirely forated corneas and globes. Meanwhile, Stocker11 re- by highly committed volunteers, also galvanized med- ported the importance of the endothelium to corneal ical individuals involved in corneal transplantation hydration while Harris and Nordquist established its around the goals of (1) ensuring quality, (2) maintain- role as an active metabolic pump,12 thus building the ing a high level of trust among eye bankers, medical body of knowledge that, among other things, would professionals, and the patients they served, and (3) inform a resurgence of interest in lamellar surgery de- establishing themselves (rather than government) as cades later. the standard bearers of quality control for their field. Toward that end, a group of leading ophthalmologists The scientific years: 1971–1999 met in 1955 during the annual meeting of what was The word “transformative” best describes the impact then the American Academy of Ophthalmology and of this time period on eye banking and on the sur- Otolaryngology (AAOO); they formed a Committee geons who transplanted corneas. The confluence of 3 on Eye Banks with the intent to standardize procure- drivers propelled the field into a new era: (1)scientific ment, preparation, and distribution procedures in the breakthroughs − a series of advances in corneal pres- United States. In 1961, this committee led to the es- ervation that broke new ground and built one upon tablishment of the Eye Bank Association of America another; (2) professionalization of eye banks − a rapid (EBAA), bringing together “lay and professional in- change from volunteerism to professionalism when dividuals dedicated to the advancement of worldwide eye banks employed executive directors, technical di- eye banking”2 and heralding a new era in corneal rectors, and certified technicians and when medical transplantation. (For a complete account of the his- standards required medical directors to take a more tory of this first eye bank association, see the related active role in eye banking; and (3) new laws and regu- article in this issue, “The Evolution of Eye Banking in lations − federal legislation prompting the emergence the United States: Landmarks in the History of the Eye of a strong leadership able to advocate for the eye Bank Association of America.”) In the field of medi- banking community. cine, ophthalmology as a practice attracted bright students to fellowships and residencies, in which physi- Scientific breakthroughs cians were required to enucleate eyes as a part of their McCarey-Kaufman (M-K) medium. The first program. significant breakthrough in short-term preservation Meanwhile, the supply of donor tissue—still be- of donor corneas emerged in the mid-1970s, some ing transplanted on an emergency basis—was not 40 years after Filatov’s seminal finding. McCarey and sufficient, and the list of patients waiting for corneal Kaufman13 reported the development of a modified transplants grew longer. Before 1968, no federal laws tissue medium (McCarey-Kaufman [M-K] medium) existed to address organ, tissue, and eye donation, and in which human corneas with viable endothelium laws differed at the state level. To attempt to make the could be preserved at 4°C for at least 4 days. The process of organ donation easier—and the same from finding hinted at the possibility for corneal transplan- state to state—the United States Congress enacted the tation to become a scheduled surgery. Wilson and Uniform Anatomical Gift Act in 1968, historic legisla- Bourne7 made note of this milestone in their 1989 tion that allowed citizens to declare themselves donors major review on corneal preservation, as “this al- for the first time.9 lowed the patient to better plan for the transplant and A surgical breakthrough occurred when Richard for the surgery to be performed when a well-trained Troutman integrated the use of the operating micro- regular team of operating personnel were available scope during corneal transplants.10 This instrument to assist a well-trained surgeon.” Corneas stored at became the standard of care for intraocular proce- 4°C in M-K medium remained thin and clear and dures, providing surgeons with greater magnification could be transported in polystyrene containers with capability, but it also created a need for more precise ice. While surgeons largely accepted the method, a surgical instruments. Troutman miniaturized and preference for transplanting corneas within 48 hours angled existing surgical tools to make microsurgery persisted. possible and reduce trauma to tissue. Corneal storage media. Meanwhile, Dough- By this time, PK had become the standard proce- man and colleagues14 at the University of Minnesota, dure for corneal transplants. Lamellar procedures had in collaboration with the Minnesota Lions Eye Bank, been tried in the 1950s, but until recently they have pursued a line of investigation that would change the

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corneal storage paradigm from preventing cell death Disease (CJD) from a donor to a healthy recipient to extending the viability of the critical endothelial was first reported.19 Subsequently, the donor was layer. Beginning in the 1970s, they pioneered the use identified as a 55-year-old who died due to clinical of 34°C organ culture as an attempt to reduce corneal symptoms of CJD at a medical center in New York antigenicity and to lengthen the period of time that and whose corneas were delivered directly to the cen- donor tissue could be stored. Over the next 2 decades, ter’s eye institute, never having passed through an eye the development of the Minnesota Corneal Storage bank. Nevertheless, the incident caused great concern System enabled the preservation of corneas at 34°C (a within the transplant community and among eye temperature comparable to corneas in vivo) in sterile, bankers. To ensure the safety of healthy donor tissue, closed containers for at least 35 days. Although re- the EBAA adopted stringent quality standards in 1978 duced antigenicity was never demonstrated, extension that became the EBAA Medical Standards. The act of endothelial viability made this medium the first established the organization as the standards-setting successful long-term donor cornea storage model. agency for eye banking in the United States.20 These The addition of chondroitin sulfate to organ culture standards continue to be updated semi-annually by in 1985 also made storage at 4°C possible, eliminat- the EBAA’s Medical Advisory Board, a collaboration ing the need for serum, which was required at 34°C.15 of medical and lay professionals that remains unique Further improvements to this simpler storage sys- among professional medical organizations and is tem led to the commercial production of Optisol by characterized by an equitable sharing of power and Bausch + Lomb,4 boosting its use among United States mutual respect. eye banks and firmly establishing corneal transplan- The EBAA also launched efforts to standard- tation as a procedure that could be scheduled. Later ize eye banking techniques, provided an intensive enhancements included the addition of the antibiotics training course to certify technicians, and began gentamycin and streptomycin, producing a medium a program for accreditation of eye banks. (These marketed as Optisol-GS; in recent years the Food and initiatives are more fully described in “The Evolu- Drug Administration (FDA) began asking the United tion of Eye Banking in the United States” in this is- States eye bank community whether an antifungal sue.) The organization also initiated scientific sym- agent should be added. Eye banks in the United King- posia that feature original peer-reviewed research dom, the Netherlands, Denmark, and France16 contin- papers focused on eye banking techniques and ued to use organ culture for extended preservation of procedures; these sessions are held twice annually corneas at 34°C; this storage method has the potential in association with EBAA conferences, including to be used in developing countries in which there are one held in conjunction with the Cornea Society.21 shortages of cornea donors. Specular microscope. Until the 1980s, eye New laws and regulations banks evaluated the suitability of donor corneas for Reimbursement changes. With Frederick Griffith transplantation using slit-lamp biomicroscopy. Intro- at the helm, a bold move by Medical Eye Bank (MEB) duction of the specular microscope and closed-cham- Inc. in Baltimore, Maryland, permanently changed ber containers to safely hold corneas separated from the business model for eye banks in the United States. globes enabled eye bankers to more carefully screen In 1971, faced with budget constraints, MEB rec- donor tissue.4 Equipped with a new tool for viewing ognized the potential inherent in the passage of the corneas at the cellular level, eye bank technicians were United States entitlement act that established the able for the first time to visualize cell morphology, Medicare program.6 The field of kidney transplanta- measure endothelial cell loss, and consistently com- tion had already tapped into the new stream of fed- pare the effects of new storage techniques.17,18 eral reimbursement for organ processing fees, open- ing the possibilities for other transplant fields. MEB’s Professionalization of eye banks Medical Director, John W. Payne, wrote in a 1980 Eye banking standards. The 1970s saw the prolif- review describing the new directions in eye banking, eration of highly organized eye banks and a technical- “Agreements were reached with the local Blue Cross ly skilled workforce that could apply new techniques and Medicare officials to accept reasonable fees billed for corneal preservation, including the growing use through local hospitals for our services. Several years of Optisol for interim storage of donor tissue and the later, similar arrangements were made in most of the monitoring of disease transmission. For example, in other states where the MEB sent donor tissue. In 1979 1974, the possible transmission of Creutzfeldt-Jakob the MEB, which previously had depended totally on

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fund raising and charity support, derived 75% of its have generally higher rates of donation,26 yet others operating budget from fees paid by third-party insur- dispute that conclusion; a systematic review of studies ers for processing costs.”6 on the impact of presumed consent legislation from Medical examiner laws. With a short-term 8 electronic databases, including MEDLINE, found method to store corneas available using M-K medium, that presumed consent alone is unlikely to explain the the Maryland eye bank decided to boost its supply of variation in organ donation rates between countries donor tissue by working with medical examiners. A with and without presumed consent systems.27 collaboration that included Payne, the state medical Required request law. To further remove bar- examiner, and concerned ophthalmologists advocated riers to donation, the United States Congress, follow- for and won passage of landmark state legislation that ing the lead of states, enacted in 1987 a revised Uni- allowed the immediate removal of corneal tissue from form Anatomical Gift Act. Among its amendments the eyes of cases under the medical director’s jurisdic- was one requiring hospitals that accept Medicare re- tion requiring autopsy—unless the next-of-kin had imbursements to notify next-of-kin of the option to specifically expressed objections to donation. In es- donate appropriate organs and tissues or to decline. sence, this legislation made it unnecessary to obtain The impact on the donor supply came to depend on consent, and most autopsied individuals could serve the how effectively hospital personnel, particularly as donors. nurses, carried out the provisions in collaboration Similar legislation was passed by 23 states by 1997, with donation organizations; the impact of the change each with varying provisions for contacting next-of- on donor pools is unclear, with some institutions orig- kin; collectively, the laws were credited with eye banks inally reporting increases and others no change.28 In receiving 15,527 corneas.22 (Morticians had already 1997, Doughman2 reported that the Minnesota Lions been found to be valuable enucleators, with successful Eye Bank experienced a tripling of cornea donations outcomes using corneas for transplantation from the following passage of the law. eye tissues they had recovered.23,24) These laws have In the United States, most states have passed first- been declared constitutional in the states in which consent legislation and established online donor reg- they have been passed, even when they do not con- istries. Donate Life America, a nonprofit alliance of tain a clause requiring the medical examiner to make national organizations and state teams, reported in a “good faith” effort to notify next-of-kin. 2011 that registrations had passed the 100 million Presumed and expressed consent. The mat- mark (42% of the adult American population). Also ter of “presumed consent” is not without controversy,25 in 2011, the EBAA began tracking the number of cor- as it typically implies that a person may be considered neal tissues recovered from donors found on a registry a donor only if he or she has not declared otherwise. or who had given first-person consent through some Many members of the transplant community argue other means; nearly 40% of recovered corneas came that the principle of “gifting” one’s eyes (indeed, any from such donors (Table 1).29 organ or tissue) implies either an active decision by FDA regulations. More than a decade after the deceased made known through a will, advance di- the EBAA established standards to ensure safety of rective, donor card (including a driver’s license in the donor tissue and had begun credentialing eye bank United States), or donor registry or else the direct per- technicians and accrediting eye banks, federal agen- mission of the next-of-kin. When the state intercedes cies began to impose regulations on eye banks. The in this principle, thereby removing actual consent, it FDA proposed a series of regulations during the 1990s raises ethical implications, even as proponents of pre- that were scientifically inappropriate for corneal tis- sumed consent legislation —sometimes called “opting- sue, nearly failed to include eye banking in provisions out” legislation—intend to ensure the most equitable that would have boosted the supply of corneal tissue distribution of organs, tissues, and eyes. A discussion to eye banks, and came close to changing reimburse- of the complex medical, legal, and ethical issues sur- ment formulas based on erroneous assumptions.4 In rounding donation and transplantation is beyond the response, leaders in the corneal transplant community scope of this discussion, especially since they remain increased their efforts to provide the education and unresolved. Many European countries and Singapore expert authority to avert or redirect the more onerous have moved toward an opt-out system, while the aspects of the regulatory effort, acquiring the experi- United States and the United Kingdom operate under ence and expertise to successfully represent the new a model of expressed, or first-person, consent. Some field in the face of regulatory threats. studies suggest that countries with presumed consent

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3. The eye banking community proved that it Table 1. Eye Banking Statistics Reported by U.S. Eye Banks: Donations, could work with federal regulatory agencies Recoveries, and Tissues Suitable for Transplantation in a constructive manner to establish proper oversight.

The modern era: 2000–present By 2000, more than 30,000 corneal transplants a year were being performed within the United States, with PK making up the majority of the procedures, according to records kept by the EBAA.31 But full-thickness corneal transplants, while capable of restoring vision, had limitations, including increased risk of postoperative complications such as wound dehiscence with blunt trauma, suture-related infections, disabling astigmatism, and graft rejection. Lamellar procedures to replace diseased layers of the recipient’s cornea, including the endothelial layer, rather than the en- tire cornea, had been attempted in the 1950s32 and had continued to be of interest in Europe; however, In 2011, the consent type is measured for the first time using the same they were technically difficult, relied on sutures, and measurement method used by Donate Life America. Eye bank poli- did not have good long-term outcomes. The first -de cies around the country vary with respect to applying donor registry cade of the new century has been notable for a series documentation as consent. When interpreting this data, it is important of advances in surgical techniques that made use of to note that six eye banks reported that none of their donors were found on a donor registry. This data does not represent the number of donors emerging technology, improved instrumentation, and recovered using donor registry documentation as consent to recover. deepening knowledge regarding the structural, genetic, and molecular makeup of corneas. Character- Adapted with permission from the 2011 Eye Banking Statistical Report by the Eye istically, entrepreneurial eye banks have ensured that Bank Association of America. Copyright ©2012 EBAA®, Washington, DC; www.restoresight.org. All rights reserved. skilled technicians can provide surgeons a safe supply of precut tissues to keep pace with the demand for these new precise procedures, which constitute vari- Transformation of the industry ous approaches to lamellar keratoplasties. As the 20th century drew to a close, eye banking and corneal transplantation professionals had achieved a Lamellar corneal surgery successful collaboration that made PK the most com- Posterior lamellar corneal surgery. The in- mon and successful form of solid tissue transplanta- troduction of posterior lamellar keratoplasty (PLK) by tion.30 In a comprehensive review published in 2000, Melles et al33 in the Netherlands in 1998 has been a sig- Chu4 named 3 major milestone achievements in the nificant advance in corneal surgery. Indeed, for many history of eye banking: surgeons, it ranks as highly as the discovery of the vi- 1. Corneal transplants could be scheduled; ability of cadaver tissue as a source for donor tissue, surgery is no longer considered an emergency. the operating microscope, and storage media allowing Chu credited improved corneal storage, better elective scheduling of corneal transplants. PLK uses instrumentation, “remarkably improved” pro- an air bubble to support the posterior lamellar graft, curement programs, and a network of eye banks thus allowing the new tissue to adhere to the graft characterized by efficient communication and recipient’s tissue, avoiding a through-and-through, transportation. 360-degree, full-thickness corneal wound, which, as 2. Surgeons could be assured of the quality and previously noted, requires multiple sutures, yields un- safety of corneal tissue. Chu cited the EBAA’s predictable visual results, and always presents a risk history of promoting training and certification for wound rupture with trauma. The evolving tech- programs for eye bank technicians, preparing niques that resulted are briefly discussed below. written policy and procedure manuals for oper- Deep lamellar endothelial keratoplasty. ating eye banks, accreditation of individual eye Terry and Ousley34 performed the first endothelial banks, and vigilance in evaluating and revising keratoplasty in the United States in 2000; they called its medical standards document. it deep lamellar endothelial keratoplasty (DLEK) and

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also used an air bubble to support the posterior lamel- technique provided superior visual outcomes but lar graft, as do all other posterior lamellar techniques. raised the bar in terms of difficulty, both in harvesting Both PLK and DLEK procedures led to faster visual donor endothelium and Descemet membrane as well rehabilitation than traditional PK and avoided many as implanting it into the eye in the correct orientation of its complications, although the techniques were with minimal trauma.” technically difficult, 35 particularly posterior trephina- Anterior lamellar corneal surgery. The tion of the recipient cornea. use of the microkeratome for posterior lamellar pro- Descemet stripping endothelial keratoplasty. cedures has been adapted for anterior lamellar kera- In 2004, Melles et al36 refined the DLEK technique by toplasty, which also is becoming an alternative to PK. peeling the recipient Descemet membrane and en- Deep anterior lamellar keratoplasty. For dothelial layer, exposing a smooth stromal posterior individuals with healthy endothelium and Descemet bed on which to place the posterior lamellar graft. membrane layers but whose vision has been impaired The technique, Descemet stripping endothelial kera- by keratoconus, stromal dystrophies, or scarring, toplasty (DSEK), was technically simpler than DLEK deep anterior lamellar keratoplasty (DALK) shows and required a smaller incision.37 Additionally, visual promise. In 2002, Anwar and Teichmann44 reported a rehabilitation time proved to be shorter. technique using a “big bubble” (of air) to separate the Descemet stripping automated endothe- Descemet layer from the deep corneal stroma. DALK lial keratoplasty. In 2006, Gorovoy38 produced a patients retain their own endothelium and Descemet smoother donor surface using the microkeratome membrane; only the anterior portion of the cornea is to dissect donor tissue, a technique he called Des- transplanted. DALK requires more time in surgery cemet stripping automated endothelial keratoplasty than other procedures and is technically challeng- (DSAEK). Visual recovery following DSAEK has ing; however, it appears to result in less postopera- been shown to be faster (weeks) compared with PK tive endothelial cell loss.45 A potential disadvantage (months).35 Use of the microkeratome in the operat- to this technique is that, as with PK, it requires mul- ing room, however, lengthened the time in surgery, in- tiple sutures along with their potential complications. volved the use of expensive equipment, and required the surgeon to have specialized skills. The drawbacks Keratolimbal allograft transplantation presented an opportunity for eye banks to streamline The success of a corneal transplant depends upon the process by training technicians to prepare precut obtaining healthy donor tissue. For posterior corneal tissue specifically for endothelial keratoplasty (EK). A disease, the endothelium is critical and is not replaced retrospective study of 913 corneal tissues prepared by by the recipient. However, for any transplant to be trained technicians in Tennessee during a 12-month truly successful, the surface epithelial cells must be period between 2007 and 2008 showed a successful replaced by the recipient’s epithelial cells. These cells preparation rate of 98.5%.39 In a study from Iowa, pre- come from the stem cells located at the ocular lim- cut tissue was found to improve safety while increas- bus. The causes of stem cell deficiency include chemi- ing surgeon efficiency.40 Lamellar dissection of donor cal burns, thermal burns, aniridia, Stevens-Johnson tissue is also possible with the more expensive femto- syndrome, ocular pemphigoid, chronic contact lens second laser, which can produce the most precise dis- wear and trauma, and multiple surgeries involving the section depths; however, the femtosecond’s dissection limbus. Although the endothelium is healthy, these plane is not as smooth as the microkeratome cut.30 conditions will not allow successful corneal trans- Due to the higher costs and unproven outcomes as- plantation unless the stem cell deficiency is corrected, sociated with use of the laser for corneal surgery,41 as allowing the cornea to regain its normal surface. well as unresolved concerns expressed by surgeons,42 A procedure developed and popularized by Hol- the femtosecond laser has so far seen limited use for land,46,47 as well as others, recovers stem cell tissue corneal transplantation. from the limbus of healthy donors and transplants Descemet membrane endothelial kerato- them directly to that of the recipient after removal of plasty. In an attempt to improve visual outcomes, diseased stem cells. Known as keratolimbal allograft Melles et al43 reported successfully transplanting bare transplantation (KLA), the procedure requires sys- endothelium on a recipient Descemet membrane in temic immune suppression since the grafted tissue 2006. The technique, called Descemet membrane en- does not share the immune privilege afforded by a dothelial keratoplasty (DMEK), holds great promise central corneal graft. Therefore, the patient must be if a number of technical challenges can be overcome. healthy enough to tolerate the regimen, although the In their review on EK, Price and Price30 noted, “The level of immunosuppression can be justified for this

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group of patients, as they are highly dependent on the Table 2. Eye Banking Statistics Reported by U.S. Banks: Distribution of Tissues survival of their grafts for functional vision.48 KLA has been able to restore useful vision for patients with severe ocular surface disease who have no other options. Recently, eye banks have explored the possibility of conserving donor tissue by splitting a single cornea into 2 sections, the first consisting of the Descemet membrane and endothelium for a patient requiring DMEK and the other providing the epithelium and stroma for a patient undergoing DALK on the same day. In 2011, Heindl et al49 published promising results using this strategy. This technique could prove especially useful for regions in which the need for corneal tissue is greater than the supply. Innovations notwithstanding and yet to come, PK still accounts for 53.5% of corneal transplants reported by United States eye banks, according to the EBAA’s The highlighted numbers reflect tissues distributed and used within most recent statistical report29 covering the year 2011 the U.S. only. Data for tissue distributed internationally in these years (Table 2). However, a preference for EK procedures is did not include by surgery type. Data from previous years included U.S. and international distribution of tissues. clearly trending. The number of penetrating grafts for corneal disease in the United States (figures not shown In 2010, Corneal Grafts Total did not include long-term preserved cor- in Table 2) decreased for the sixth straight year, from neal tissue. In 2011 and progressing, long-term preserved corneal tis- 42,063 in 2005 to 21,620 in 2011. The number of EK sue is included in the total. procedures rose to 21,555, a 12.5% increase over 2010 Adapted with permission from the 2011 Eye Banking Statistical Report by the Eye and 18.3% over 2009. EK has become the surgical Bank Association of America. Copyright ©2012 EBAA®, Washington, DC; treatment of choice for corneal endothelial failure and www.restoresight.org. All rights reserved. is expected to exceed the number of PK procedures within the United States in 2012.29

The unknown future: present−? ARE WE PREPARED This trend appears to be continuing with the introduc- FOR WHAT’S AHEAD? tion of Descemet membrane automated endothelial keratoplasty (DMAEK).50,51 Furthermore, rapidly ex- n reviewing the last 100 years of milestones in eye panding research into surgical and nonsurgical tech- I banking and corneal transplantation, 5 strengths niques involving artificial corneas, xenotransplanta- emerge that distinguish the community. These can be tion, collagen cross-linking, amniotic membranes, summarized as follows: stem cells, genetic engineering, or cutting-edge phar- 1. Commitment to the highest standards. The in- maceuticals such as vaccines and eye drops promises ternal drive of eye banking and medical profes- even more dynamic advances for treating corneal pa- sionals to hold ourselves to the highest possible tients, some of which may preclude the need for sur- standards is second to none and imbues the gery as we now know it. These innovations will inevi- field with authority. tably have a dramatic impact on eye banking. 2. Cooperation. Mutual trust and respect between medical professionals and eye bankers have fostered the productivity to which private enterprises aspire. 3. Innovation and application. Our field has a long and rich tradition of innovating and mov- ing advances into practice for the benefit of patients. 4. Global mindset. Long before “globalization” became a buzzword, eye bankers and medical professionals were sharing information,

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discoveries, and resources across borders while is generated and spent, and it is safe to say that the remaining realistic about our capabilities. American healthcare system will continue to be in the 5. Leadership and advocacy. Challenges and political crosshairs for a long time to come. threats have galvanized the field, allowing our At the same time, the fragility of the current eco- leaders to speak with credible authority. nomic recovery from an unprecedented period of These strengths provided a strong foundation upon economic volatility, unemployment, mortgage indus- which our field could mature, and they will be pro- try collapse, and sovereign debt crises leaves few un- foundly needed as we enter the next era. touched financially. Who in the long run will be able For all of the progress of the past century, the fact to afford to receive—or deliver—healthcare is an open remains that millions of men, women, and children question. What will be the impact of the worldwide worldwide experience blindness from corneal dis- economic crisis, the pace of economic recovery, un- ease or injury, the largest proportion of whom live in checked healthcare costs, and fluctuations in the polit- countries with developing economies. In one estimate ical will to fund (or not fund) breakthrough research? of the number of blind people in the world—some 50 Who will be able to afford new technology, new drugs, million—corneal diseases ranked as the second most and new procedures in the years to come? How will important cause.52 And of an estimated 1.4 million the business of eye banking and the profession of oph- children globally who are blind, corneal pathology thalmology change in the next 5 or 10 years? was reported to be the cause for 20% of them.53 How Government efforts to impose regulations in the do we bring the benefits of cornea transplantation to field of cornea transplantation warrant close scrutiny. a greater proportion of patients, especially in these Regulations can increase costs, particularly adminis- times of economic upheavals, not to mention unprec- trative and reporting costs, without improving quality. edented demographic, socioeconomic, geopolitical, Legislation that increases the availability of donor tis- biological, regulatory, technological, cultural, and sue has merits, as do training programs that enhance ethical challenges? the ability of hospital and hospice staff to encourage The intent of this section is to raise the important families to allow donation of loved ones’ corneas. questions that must be addressed and to point to any strengths and assets available to the eye banking com- Demographic trends munity as we attempt to answer these questions. Every The situation is further complicated by an aging popu- effort has been made to present the challenges ahead lation, certainly within the United States. By 2030, the from an international perspective wherever possible proportion of the American population in the work- and when verifiable information has been available. ing age group (ages 21−64) will drop to 55% from 60% That said, examples from the United States, as they are in 2010.55 The numbers of Medicare recipients will in- familiar to the author, play a large role in the following crease commensurately, driving up costs, unless po- discussion. litically unpopular measures to the contrary are taken. What affects Medicare coverage in the United States Healthcare economics inevitably affects reimbursement at large. Whether or The complexity of healthcare economics is beyond not Medicare covers corneal transplantation proce- the scope of this review, although the topic can be ig- dures in the future, federal spending on healthcare is a nored only at our own risk. Internationally, the World powerful force in the United States, influencing every- Health Organization (WHO) is advocating for univer- thing from funding for research, specialties selected, sal healthcare coverage in all countries.54 In the United the balance of preventive care vs. treatment, which States, such a goal gained traction in the healthcare re- pharmaceutical advances are developed, and more. form measures passed in March 2010 (“Obamacare”). The aging of the baby boomers could also have These reforms have been a lightning rod for political an impact on the donor pool. For 2011, the EBAA29 opposition, with a sizable number of Congressional reported the donation of 114,348 whole globes and representatives elected in 2010 having campaigned corneas to United States eye banks, compared with on overturning the measures. The current political 110,630 in 2010 and 107,289 in 2009; this was the climate, characterized by intense opposition to federal third year in a row that more than 100,000 recover- spending (i.e., the Tea Party movement) and mount- ies were made in a single year. Fully 70% of donors ing frustration with economic disparities (i.e., the Oc- were between the ages of 51 and 80 years old at the cupy Wall Street movement), is bringing more and time of their death. In 2011, the “leading edge” of more scrutiny to how revenue in the United States the baby boomers entered the 65- to 69-year-old age

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group, according to the Census Bureau.55 This same or artificial corneas. However, they can be used for en- age group forms a portion of the age category (ages dothelial lamellar keratoplasty, KLA, or patch grafts. 61−70) that accounted for 32% of cornea donors in Unfortunately, refractive procedures cannot al- 2011.29 ways be detected in donor eyes, and families may not As the bulge of baby boomers advances, the Census remember or know whether the donor had LASIK.4 Bureau projects that by 2030, nearly 1 in 5 Americans The EBAA 2011 Statistical Report notes that LASIK will be age 65 or older. Will they be donors, recipi- is expected to have an impact on the donor popula- ents, or both? Eye banks would be well advised to (1) tion, although at this time a large percentage of LASIK ensure this population group is well informed about patients are living.29 If LASIK continues to grow in their ability to donate corneas, (2) encourage agree- popularity and affordability, so will its impact on the ment about a donor’s wishes among family members, donor supply. As yet unanticipated innovations in cor- who are often conflicted and may refuse to donate neal surgery may have similar inhibitory impacts on tissue if they are unsure of a relative’s wishes, and (3) the donor supply. work collaboratively with professionals involved in Add to the demographic situation the fact that, due the donation process such as healthcare professionals, to a lack of financial support, there has been no ap- medical examiners, and funeral directors. preciable expansion in ophthalmology residencies for Corneal surgeons and eye bank professionals years. A highly discussed report from the RAND Cor- should continue to examine the data regarding the vi- poration in 199860 concluded that ophthalmologists ability of transplanting older corneas,56,57 particularly were in “oversupply,” but did not take the baby boom- in light of evidence suggesting that surgeons continue ers into account. Will there be enough physicians to show a preference for corneas from younger donors. trained in corneal transplantation—and specifically in A 2008 report58 from the Cornea Donor Study Investi- eye banking—to meet the needs of greater demand? gator Group noted that whether donor age should be All of the advances in surgical techniques will not help used to determine suitability of a cornea for transplan- if there are too few surgeons to use them. Efforts need tation has been an area of considerable controversy to be undertaken to (1) ensure funding to train physi- among corneal surgeons in the United States, and it cians and (2) recruit highly talented students into the analyzed whether graft survival over a 5-year period specialty, particularly those students interested in the using corneal tissue from donors older than 65 years kind of collaboration with eye bank professionals that is similar to graft survival using corneas from younger has made the field so strong. donors. The primary finding was that clear graft rates at 5 years were the same for both older and younger Diversity of beliefs donors (86%). A recently released report from the Immigration issues within the United States and else- same study group retrospectively evaluated whether where have been growing more contentious in re- these findings had led to changes in transplantation of cent years, with some factions arguing that a country corneas from older donors and concluded there had is strengthened by a diversity of beliefs and cultural been a modest overall increase in the donor age of cor- practices and other voices expressing concern about neas transplanted in the United States from 1998 to refugees and undocumented workers taking jobs that 2009; the authors argue for wider acceptance of older might otherwise go to native citizens. Europe has re- tissue.59 Continuing to build the body of knowledge peatedly grappled with the issue, watching violence around this question should be a priority. erupt when such tensions heated up. Any resolution Another factor that will limit the donor pool is the of immigration matters may be a long time in com- prevalence of donors who have undergone laser in situ ing. Meanwhile, it would be wise for eye banking and keratomileusis (LASIK), a commonly performed re- medical professionals to (1) be familiar with the va- fractive surgery, which restricts the suitability of cor- riety of groups and related belief systems comprising neas for use in certain types of transplant procedures. the population of their geographic region and (2) help LASIK correction for myopia, for example, flattens professionals who are securing donation agreements the surface of the cornea and thins the stroma. Thus, when known concerns about donation are due to the corneas that have undergone LASIK are unsuitable influence of faith-based, ethnic, or cultural groups. for PK due to potential splitting of the corneas during It is critical to guard against misunderstanding or surgery; even if corneas do not split, flattening of the misinterpreting convictions held by individuals with anterior surface creates unpredictable visual results. different worldviews. In South Texas, for example, LASIK-treated corneas also cannot be used for DALK The Texas Tribune61 featured a report noting that a

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common practice among the large Hispanic popula- A summary of the views on donation and trans- tion in the area is to honor the deceased and their fam- plantation from prominent as well as lesser-known ilies with open-casket viewing. A barrier to organ and religious groups can be found in Organ and Tissue Do- tissue donation has been a deeply imbedded cultural nation: A Reference Manual for Clergy, developed for fear that donation will render a body unsuitable for transplant professionals and clergy who work in the viewing. To boost donation rates, the federally funded hospital, parish, clinic, or classroom setting.68 A recent Texas Organ Alliance determined its target audience report from the United Kingdom provides an over- to be 18- to 36-year-olds, who were perceived to be view of key issues related to death rituals and religious young enough to entertain a fresh point of view. faiths and how they impact donation, with the goal Donate Life America has taken steps to raise aware- to help procurement staff deal more effectively with ness about such multicultural issues related to dona- recently bereaved families.69 A WHO report released tion.62 Its primary goals are to facilitate high-perform- in October 2003 mentioned religious, cultural, and ing donor registries, develop and execute multimedia ethnic factors that influence corneal transplantation donor education programs, and motivate Americans rates in African, Asian, and Latin American countries to register as organ, eye, and tissue donors. In May and at the same time examined more “scientific” is- 2011, Donate Life partnered with Facebook in an ef- sues such as the infrastructure and paucity of trainer fort to dramatically increase the number of Americans personnel, oversight mechanisms, and lack of legisla- who officially designate themselves as donors. tion and research.70 On the other side of the planet, Yew et al63 found that 67% of participants in randomly sampled house- Natural and man-made disasters holds in Singapore were willing to donate their cor- Clearly, the challenges ahead will vary by culture and neas. Chinese ethnicity and religious affiliation with by region, although we must also keep in mind that Christianity, Hinduism, or no religion were associated we live and work in a world of unprecedented inter- with increased willingness to donate. Respondents connectedness. Moreover, economies throughout the least willing to donate were Malays and Muslims. world are linked, and volatility and uncertainties in Among respondents unwilling to donate, 73.2% said one region will, sooner or later, touch another. While they believed it was important for the body to remain advanced surgical techniques may be more accessible intact after death. in countries with developed economies, for example, Shaheen and Souqiyyeh64 addressed Islamic views such surgeries depend on the availability of pharma- and specific barriers to donation among Muslim do- ceuticals with ingredients increasingly produced in nors in Saudi Arabia. Although selling organs is for- countries with developing economies. All it takes to bidden, donating to genetically related individuals or interrupt a precarious supply chain is a natural disas- spouses is permitted. The authors said obstacles to do- ter, civil unrest, or even the discovery of contamina- nation include (1) inadequate numbers of emergency tion of a critical ingredient. This occurred in 2008 rooms, paramedics, and neurologists, (2) late report- when the FDA71 alerted healthcare providers of the ing of deaths for fear of uncovering medical mistakes, recall of the critical anticoagulant heparin, most of and (3) pervasive lack of awareness about brain death. which was produced in China. Ultimately, a reduced Many religious groups support organ and tis- heparin supply became dire enough that the United sue donation so long as it does not hasten the death States General Accountability Office (GAO) was asked of the donor. Buddhism, for example, teaches that, to investigate the crisis. In its report to Congress, the in his previous lives, the Buddha repeatedly gave his GAO pointed out that the FDA had “faced some limi- body or parts of his flesh to others.65 Sri Lanka, where tations in its efforts to inspect heparin firms in China about 70% of the population is Buddhist, has become and collaborate internationally.”72 an exporter of corneas; many Sri Lankans believe that An example from the eye banking community surrendering their eyes at death completes an act of occurred when Bausch + Lomb ran low on corneal “dana,” or giving, which helps them to be reincarnated viewing chambers (CVCs) and eye banks had to resort into a better life.66 In South Korea, a celebrated Roman to using vials to store corneal tissue, which had be- Catholic cardinal who died in 2009 donated his eyes; come an outdated practice given the preference to use subsequent media coverage was shown to increase CVCs to measure corneal layer thickness after precut- cornea donation, according to a recent modeling ting. The situation points out how reliant eye banks analysis, which concluded that religious leaders who are on very few suppliers for key products that are achieve celebrity status can positively affect public unique and necessary for eye banking. Yet to control health.67

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spending, healthcare facilities (like all big industries) century forces that threaten to restrict access to care have moved away from stockpiling regularly used sup- and limit the donor pool. plies (e.g., pharmaceuticals, electronics, infection con- Are we prepared for the complex challenges ahead? trol equipment, even food). They seem daunting and unpredictable, with permu- As a result of globalization, just-in-time order- tations few of us might even be able to imagine. The ing73,74 keeps inventory costs down and is generally answers surely lie in the traditional strengths of our more efficient. However, this trend puts critical sup- community: commitment to the highest standards, plies needed for surgery in jeopardy, as what have innovation, cooperation, leadership, and advocacy. As become “long and thin” supply chains could be easily this discussion hopes to make clear, we must further interrupted by disasters brought on by nature, human develop our global mindset, and we must develop it activity, or accidents. The 2009 H1N1 influenza pan- aggressively and quickly. demic, for example, created a worldwide shortage of While eye banking and medical professionals, N-95 respirators and surgical masks. A more devas- long united in the pursuit of high quality and acces- tating pandemic could affect the supply of electrical sibility, should build on that history of collaboration, power, making rationing necessary.75 The 2011 earth- taking steps to preserve and protect it, it is likely that quake, tsunami, and resulting nuclear disaster in Japan each eye bank will prepare for our uncertain future in brought manufacturing of some cars to a standstill. its own way, depending on its size and location. But Intentional acts of terrorism, such as the 9/11 disaster, make no mistake: each eye bank must prepare. Per- stopped air transport for days. The impact of disasters haps the launch of the International Journal of Eye on elective surgeries such as corneal transplants could Banking will provide eye banking and medical pro- be chilling. fessionals with a valuable forum for discovering and discussing cost-effective, regionally useful solutions, Ethical dilemmas not only over time but even—through electronic me- As advances in gene therapy, xenotransplantation, and dia—in real time. Our goal as a community should be stem cell use continue, the eye banking community to tackle the compelling questions head on, not shirk- will encounter ethical concerns that have yet to rise to ing from them but seeking profoundly new avenues a contentious level. Additionally, as cost-control pres- to restore eyesight whenever and wherever we can. sures squeeze healthcare delivery further, rationing of care may become an increasingly important issue, es- Acknowledgment pecially as accelerating demographic changes drive up The authors would like to thank Kathleen Kimball- utilization rates. The growth in medical tourism also Baker for her help researching the literature and for poses ethical concerns, as patients from affluent coun- writing assistance. tries travel to countries with emerging markets that offer modernized healthcare facilities at lower cost. Some observers question whether it is fair or appro- REFERENCES priate for wealthier patients to save money by utiliz- ing medical resources that should be directed toward 01. Zirm E. Successful total keratoplasty. Graefes Arch Klin a country’s native population. Exp Ophthalmol. 1906;64:581. 02. Doughman DJ. Corneal tissue preservation, chapter 34. In: Leibowitz HM, Waring GO. Corneal Disorders: DISCUSSION Clinical Diagnosis and Management. 2nd ed. Philadel- phia, PA: WB Saunders Co.;1998:871-882. he numerous advances in corneal transplanta- 03. Filatov VP. Transplantation of the cornea from pre- Ttion and eye banking over the last century have served cadavers’ eyes. Lancet. 1937;229:1395-1397.0 produced—for most developed countries—a plenti- 04. Chu W. The past 25 years in eye banking. Cornea. ful supply of safe donor tissue, the ability to schedule 2000;19(5):754-765. surgery rather than react on an emergency basis, and 05. Moffatt SL, Cartwright VA, Stumpf TH. Centennial new and better tools. However, those advances have review of corneal transplantation. Clin Experiment yet to reach all of the patients who could benefit from Ophthalmol. 2005;33(6):642-657. them, and the humanitarian goal to deliver safe cor- 06. Payne JW. New directions in eye banking. Trans Am neas and ever more sophisticated surgical techniques Ophthalmol Soc. 1980;78:983-1026. to far-flung regions of the world is hampered by 21st 07. Wilson SE, Bourne WM. Corneal preservation. Surv Ophthalmol. 1989:33;4.

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